The main goals of this proposal is to explore the role of membrane death receptors and their ligands in nonsteroidal anti-inflammatory drugs (NSAIDs) and ionizing radiation (IR)-induced apoptosis in human prostate cancer cells. Evidence suggests that the regular use of NSAIDs reduces the risk of other cancer types but their role in prevention of prostate cancer has not been elucidated. NSAIDs are believed to mediate their chemopreventive and anti-tumorigenic effects by inducing apoptosis. IR is an important therapeutic modality against prostate cancer and is believed to kill prostate cancer cells by inducing apoptosis. However, the biochemical and molecular pathways via which these agents induce apoptosis have not been fully elucidated. Preliminary results presented in this proposal indicate that sulindac sulfide, a clinically relevant NSAID, induces apoptosis in human prostate cancer cells. Sulindac sulfide also augments ionizing radiation (IR)-induced apoptosis in human prostate cancer cells. Preliminary evidence presented in this application further suggests that death receptor 5 (DR5) may be involved in transducing the apoptotic signals of sulindac sulfide and IR. Thus, the role of DR5 and its ligand in this context will be explored. Similarly, the contribution of other death receptors and their ligands in sulindac sulfide, IR and sulindac sulfide+IR-mediated apoptosis will be investigated. DR5 activation stimulates apoptotic pathway and NF-kB-dependent survival pathway. IR activates NF-kB while sulindac is known to inhibit NF-kB. Thus, the role of NF-kB in sulindac sulfide-induced radiosensitization will also be explored. The long-term objectives of this proposal are to (i) better understand the apoptotic signaling pathways in human prostate cancer cells and (ii) lay the ground work to potentially develop a novel treatment and/or prevention strategy against this deadly disease.